Cytokines, such as stem cell factor, interleukin 3 and thrombopoietin, control the physiology of hematopoietic stem cells, and in particular their survival and expansion. However, the underlying mechanisms are poorly understood. Over the past several years researchers have identified transcription factors from the family of Signal Tansducers and Activators of Transcription (STAT) as key mediators of cytokine signalling. We have deleted the transcription factors Stat5a and Stat5b from hemeatopoietic stem cells in the mouse and discovered that loss of these transcription factors results in stem cells that are unable to efficiently populate bone marrow. In collaboration with others it was determined that hematopoieitc stem cells in the absence of Stat5 are not competitive. Moreover, development of several hematopoietic lineages is severely compromised. We are currently in the process of defining the mechanism by which the cytokine thromopoietin (TPO) controls the fitness and self-renewal of hematopoietic stem cells.